Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems

Introduction: Aside to changes in personality and behavior, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. Only little is known about the underlying mechanisms leading to the anatomical constraints of the pathophysiology. Here, we evaluated if these alterations are linked to the distribution of specific neurotransmitter systems.Methods: Maps of fractional amplitude of low frequency fluctuations (fALFF) were derived as a measure of local activity from resting state functional magnetic resonance imaging for 52 bvFTD patients and 22 healthy controls (HC). We tested if alterations in the fALFF signal of bvFTD patients co-localize with the known non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of this co-localization is associated with respective symptom severity.Results: Compared to HC, patients displayed significantly reduced fractional amplitude of low frequency fluctuations in fronto-temporal and fronto-parietal regions. These alterations significantly co-localized with the distribution of serotonin (5-HT1b, 5-HT2a), dopamine (D2), and gamma-aminobutyric acid type A receptors, the noradrenaline transporter, and their encoding mRNA gene expression. The strength of the co-localization with D2 and noradrenaline transporter was associated with cognitive symptoms of bvFTD. Conclusion: Local brain functional activity reductions in bvFTD follow the distribution of specific neurotransmitter systems supporting the notion of the preferential vulnerability of specific neurotransmitter systems. These findings provide novel insight into neuropathophysiological mechanisms underlying functional alterations in bvFTD